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Phase 3 Comparison Trial: GLP-1 vs DPP-4

Sep 17, 2019
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Adam Chalela, B.S. Doctor of Pharmacy Candidate USF College of Pharmacy

GLP-1 vs DPP-4: a recent study demonstrates the efficacy of a new, once daily oral option for patients with type 2 diabetes already on metformin. 

The overall treatment goal for patients with type 2 diabetes is to maintain adequate glycemic control. Many classes of medications to control blood sugars have emerged over the past 20 years, specifically glucagon like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, which are incretin based therapies. Multiple medication options have been developed in each of these classes of medications in attempts to outperform the last with respect to safety and efficacy outcomes.

In previous studies, GLP-1 receptor agonists have demonstrated a greater efficacy of glucose and body weight lowering ability when compared to their DPP-4 inhibitor counterparts. Traditionally, GLP-1 receptor agonists are administered via subcutaneous injection due to their rapid pH-induced metabolism within the stomach. However, a novel GLP-1 receptor agonist has recently come to market as an oral tablet to be taken by mouth once daily. A recent phase 3 study has compared the long-term safety and efficacy of this oral GLP-1 receptor agonist, semaglutide, to sitagliptin, a widely used DPP-4 inhibitor that has already demonstrated its glucose lowering ability in previous studies.

The comparison of semaglutide to sitagliptin as add on therapy to metformin in patients with type 2 diabetes was conducted through a multicentered, randomized, double blind, active controlled, 78 week long study. Patients were enrolled into this study if they had an active type 2 diabetes diagnosis, an HbA1c of between 7 and 10.5, and on a stable dose of metformin. Patients were excluded if they had recent therapy changes for the treatment of type 2 diabetes or obesity, or had a history of pancreatitis or any secondary vascular complication to diabetes (i.e. retinopathy or kidney disease).

In this study, patients were treated with varying doses of semaglutide (3mg, 7mg, and 14mg daily) or a fixed-dose of sitagliptin (100mg daily) randomized in an equal fashion. Previous phase 2 studies have demonstrated the impaired absorption of oral glucose lowering therapies with food, leading to the administration of study drugs during a fasted state with adequate amounts of water and prior to administration of any other oral medication throughout this trial. The primary endpoint in this study was net change in HbA1c while net change in total body weight was measured as a secondary endpoint. Both efficacy endpoints were included in primary analysis and were measured from baseline throughout week 26; all secondary endpoints were measured every 26 weeks thereafter. Safety data such as total incidence of serious adverse events such as symptomatic hypoglycemic episodes were also recorded.

A total of 1,864 patients were enrolled into this study, 466 of each randomized to each treatment group. Baseline characteristics were homogenous between treatment groups: the average patient was a 58 year old white male who had diabetes for 8.6 years with an HbA1c of 8.3% and body weight of 91.2 kg (200.64 lb). Patients randomized to receive 7 mg and 14 mg of semaglutide daily showed significant superiority in HbA1c reductions from baseline to week 26 when compared to those treated with sitagliptin; absolute relative differences of -0.3% (95% CI 0.4% to -0.1%) and -0.5% (95% CI -0.6% to -0.4%), respectively. Similar statistically significant trends were observed in overall body weight reductions as well. Patients treated with 7 mg of semaglutide daily had an absolute relative difference of -1.6 kg (95% CI -2.0 to -1.1 kg) while patients treated with 14 mg of semaglutide daily had an absolute relative difference of -2.5 kg (95% CI -3.0 to -2.0 kg). Patients randomized to receive 3 mg of semaglutide daily failed to demonstrate non-superiority to sitagliptin in both primary and secondary endpoints. All exploratory endpoints, such as change in HbA1c from baseline to week 78, demonstrated similar outcomes. Rates of adverse events were similar between all treatment arms as they are both incretin based medications.

Practice Pearls

  • Optimal doses of semaglutide demonstrate significant superiority over sitagliptin with regards to both HbA1c lowering and body weight reducing abilities.
  • Semaglutide is an oral GLP-1 inhibitor that is a strong candidate for add-on therapy in patients with diabetes already on metformin whose goal is to lose weight.
  • Clinicians should consider semaglutide for patients with diabetes who wish to avoid injectables or are non-adherent to them.


Reference for “Phase 3 Comparison Trial: GLP-1 vs DPP-4”:

Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: the PIONEER 3 randomized clinical trial. JAMA 2019; 321(15):1466-1480. DOI: 10.1001/jama.2019.2942

Adam Chalela B.S., PharmD Candidate, USF College of Pharmacy Class of 2020


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